647 ture of stereoisomers. This mixture was promptly subjected to oxidative cleavage with lead tetraacetatelo (EtOAc/pyridine, 25 “C, 20 min) and, after purification by chromatography on silica (elution with 1:l benzene-ethyl acetate), a 54% yield (based on 12) of 14 (3500, 1728, 1708 cm-l; d 1.50 (9 H , s), 2.18 (6 H, s), 6.58 (1 H , d , J = 16 Hz), 6.64 ( 1 H , d , J = 16 Hz), 6.96 ( 1 H, d, J = 16 Hz), 7.06 (1 H, d, J = 16 Hz)) was obtained. Mild hydrolysis of 14 (TFA, 0 O C , 15 min) furnished the highly polar carboxylic acid 15, which provided the substrate for subsequent lactonization studies. Virtually all lactonization methods currently in vogue entail activation of the carboxyl group, followed by nucleophilic attack by hydroxyl.Il Although this tactic has enjoyed noteworthy success in macrolide synthesis,2,12the sensitive enedicarbonyl functions in 14 frustrated all attempts to construct suitably activated ester derivatives. Consequently, we turned to an approach in which the roles of carboxyl and hydroxyl partners are reversed, adopting the principle of hydroxyl activation in the presence of a carboxyl group as nucleophile.13 Thus, treatment of 14 in benzene with triphenylphosphine, followed by diethyl azodicarboxylate with vigorous stirring (25 O C , 2 days),I4 gave, after preparative thin-layer chromatography on silica, a 15% yield of (f)-vermiculine (l), identical by infrared, N M R , mass spectral, and chromatographic comparison with authentic material. A slightly more polar, chromatographic fraction corresponding to the unnatural, trans isomer of 1 was also isolated. Although the yield of 1 from 14 is disappointingly low, the lactonization method demonstrated here provides a potentially useful alternative to the conventional carboxyl-activation methodo10gies.l~ Considerable refinement of this “reverse activation” technique may be anticipated.16
Acknowledgment. We are grateful to Professor Robert K. Boeckman, Wayne State University, for a sample of natural vermiculine. References and Notes (1) R. K. Boeckman, J. Fayos. and J. Clardy, J. Am. Chem.
(15) A study of the generality of this lactonization method has recently been reported (T. Kurihara, Y. Nakajima, and 0. Mitsunobu, Tetrahedron Lett.,
2455 (1976)). (16) This work was supported financially by the National Institutes of Health (AI 10964). (17) Recipient of a National Institutes of Health Research Career Development Award.
Yoshiyasu Fukuyama, Curtis L. Kirkemo, James D. White*” Department of Chemistry, Oregon State University Corvallis. Oregon 97331 Received October 15, I976
A Comparison of the Heterolytic vs. Homolytic Cleavage of the Nitrogen-Chlorine Bond Sir: Over the last decade, we have carried out a detailed study of the reactions and properties of nitrenium ions (divalent positive nitrogen species).’ As part of these investigations, we described the heterolytic cleavage of the N-Cl bond of Nchloramines in both silver ion promoted and purely solvolytic ionization reactions. However, recently it was stated that “Nitrenium ions are not generated from simple secondary chloramines in the presence of silver ions at room temperature.”2 Extrapolations of this statement3 have prompted us to thoroughly establish the difference between the heterolytic and homolytic cleavage of the N-C1 bond of chloramines. We now wish to report the details of this study. In our early work on the rearrangement of N-chloramines, we established that both the silver-ion promoted and noncatalyzed solvolysis of 1 in methanol gave a mixture of 2,3, and 4.4It was proposed that the formation of 3 and 4,which con-
SOC., 96, 5954
(1974). (2) An identical ring system is present in the antibiotic pyrenophorin: E. W. Colvin, T. A. Purcell. and R. A. Raphael, J. Chem. Soc.. Perkin Trans. 1,
1718 (1976). (3) E. J. Corey, K. C. Nicolaou. and T. Toru, J. Am. Chem. SOC., 97, 2287 (1975). (4) SatisfactMy elemental compositions foc isolated compounds were obtained by accurate molecular weight determination, using a CEC-1O3B mass spectrometer. (5) R. Deghengi and C. R. Engel, J. Am. Chem. SOC.,82,3201 (1960). (6)R. K. Callow, E. Kodicek, and G. A. Thompson, Proc. R. SOC.London, Ser. E, 184, l(1966). (7) Prepared from a-bromoacetyl bromide and teff-butyl alcohol in the presence of N,Ndimethylaniline (ether, 0 OC), as described for the a-chloro ester (R. H. Baker. “Organic Syntheses”, Coli. Voi. 111, Wiiey, New York, N.Y.. 1955, p 144). (8) A. V. Dombrovskii and V. A. Dombrovskii, Russ. Chem. Rev., 35, 733 (1966). (9) H. 0. House, “Modern Synthetic Reactions”, 2nd ed, W. A. Benjamin, Menlo Park, Calif., 1972, p 306. (10) H. R. Goldschmid and A. S. Perlin, Can. J. Chem., 38, 2280 (1960). (1 1) Inter alia (a) anhydrides (D. Taub, N. N. Girotra, R. D. Hoffsommer, C. H. Kuo, H. L. Slates, and N. L. Wendler, Tetrahedron, 24, 2443 (1968); H. L. Wehrmeister and D. E. Robertson, J. Org. Chem., 33, 4173 (1968); see also P. M. Baker, B. W. Bycroft, and J. C. Roberts, J. Chem. SOC.C, 19 13 (1967); and 0. C. Musgrave, R. Templeton, and H. D. Munro, ibid., 250 (1968);(b) imidazolides (J. D. White, S . N. Lodwig. G. L. Trammell, and M. P. Fleming, Tetrahedron Lett., 3263 (1974));(c) 2-pyridyl thioesters (E.J. Corey and K. C. Nicolaou, J. Am. Chem. Soc., 96, 5614 (1974));(d) teffButyl thioesters (S.Masamune, S.Kamata. and W. Schilling, J. Am. Chem. Soc., 97, 3515 (1975));(e) 2-acyloxypyridinium salts (T. Mukaiyama, M. Usui. and K. Saigo, Chem. Lett., 49 (1976)). (12) S.Masamune, H. Yamamoto, S . Kamata, and A. Fukuzawa. J. Am. Chem. SoC., 97, 3513 (1975); E. J. Corey, K. C. Nicolaou, and L. S.Melvin, ibid.,
’H 1
2
3
4
stituted greater than 90% of the product mixture arose via Wagner-Meerwein rearrangement of the initially generated nitrenium ion 5 to yield the carbonium ion 6. Addition of solvent or internal return of chloride would then give 3 or 4, respectively. In order to distinguish between a homolytic and a heterolytic cleavage of the N-Cl bond, it became necessary to generate the amino radical, 7, and to compare the products derived from 7 with those arising from the solvolytic reactions previously studied. Three approaches were taken to the generation of 7. These were (1) photolysis of the tetrazene 8, (2) photolysis of 1, and (3) benzoyl peroxide promoted decomposition of 1 in methanol.
97, 654 (1975). (13) This approach was used successfullyin a recent, total synthesis of nonactin for the stereospecific coupling of nonactic acid residues. However, final lactonization to the macrotetrolrde was accomplished using pyridyl thioester activation (U. Schmidt, J. Gombos, E. Haslinger, and H. Zak, Chem. Ber.,
109. 2628 (1976)). (14) 0. Mitsunobu, M.’Wada, and T. Sano, J. Am. Chem. SOC.,94,679 (1972); A. K. Bose, B. Lal, W. A. Hoffman, and M. S. Manhas, Tetrahedron Lett.,
1619 (1973).
5
7 6
Communications to the Editor
648 Tetrazenes are well-established sources of nitrogen radicals5 In order to prepare the tetrazene necessary for the production of 7 , 2 was treated with nitrosyl chloride to give 9,6 which on lithium aluminum hydride reduction gave the hydrazine 10.
\H
9
+ I
2
These results clearly indicate that the benzoyl peroxide-induced decomposition of 1 in methanol has a radical-chain component. In summary, we have demonstrated that nitrogen radicals can follow reaction paths, which are very diverse from those of nitrenium ions. Specifically, in the case studied, we have shown that while the imine 11 was completely absent in the methanolysis of 1, it was a major product of all of the reactions, which should proceed via the nitrogen radical 7. This indicates that both the silver ion promoted and noncatalyzed methanolysis of l proceed via heterolytic cleavage of the N-CI bond as previously p r o p o ~ e d . ~ . ~
Acknowledgment. W e are indebted to the National Cancer Institute of the Public Health Service for Grants CA-07110 and CA-17269 which supported this investigation. References and Notes 10
8
Oxidation of 1 0 with mercuric oxide gave the tetrazene 8 in 60% overall yield. Irradiation of a methanolic solution of 8 a t room temperature with a Hanovia 450-W high pressure mercury lamp gave only 2 and 1 1 in 63 and 34% yields, respectively. No products derived f r o m skeletal rearrangement could be detected. The structure of 2 was established through comparison with an authentic sample. The structure of 11 was assigned on the basis of its N M R spectrum (single olefinic proton at 6 7.50) and through comparison with an authentic sample prepared from 1 by treatment with sodium methoxide.
8
\ H
For a leading reference see P. G. Gassman, Acc. Chem. Res., 3, 26 (1970). 0.E. Edwards, D. Vocelle, and J. W. Apsimon, Can. J. Chem., 50, 1167 (1972). See also 0. E. Edwards, G. Bernath, J. Dixon, J. M. Paton, and D. Vocelle, ibid., 52, 2123 (1974). For example see R. N.Haszeldine. T. J. Tewson. and A. E. Tipping, J. Fluorine Chem., 8, 101 (1976). P. G. Gassman and R. L. Cryberg, J. Am. Chem. SOC., 90, 1355 (1968); 91, 2047 (1969). F. 0. Rice and C. J. Grelecki, J. Am. Chem. SOC.,79, 2679 (1957); J. S. Watson and A. J. Waring, Can. J. Chem., 38,298 (1960); J. S. Watson, J. Chem. Soc., 3677 (1956); A. Good and J. C. J. Thynne. J. Chem. SOC.B,684 (1967); C. J. Michejda and W. P. Hoss, J. Am. Chem. SOC., 92, 6298 (1970). Satisfactory elemental analyses or exact mass molecular weights were obtained on all new compounds. In all cases spectroscopic data were consistent with the assigned structure. In control experiments, it was demonstrated that while a large excess of hydrogen chloride catalyzed the decomposition of 1 to give only 2 (as its hydrogen chloride salt), the hydrochloride of 2, as generated in the normal course of the reaction, did not promote perceptible decomposition of 1 in the time required for the photochemical decomposition. These results raise questions concerning the role of "heavy atom solvent effects" in the interconversion of singlet and triplet nitrenium ions.' Since the amino radical 7 clearly yielded both 2 and 11, the failure to identify 11 as a major product of the decomposition (solvolysis) of 1 in heavy atom solvents indicated that a major difference existed between the cationic nitrogen diradical (nitrenium ion triplet), the nitrogen cation radical (previously postulated as an intermediate in the reaction of triplet nitrenium ions with hydrogen donating solvents), and amino radicals such as 7. Further studies of these differences and of the general concept of "heavy atom effects" in nitrenium ion chemistry are currently under investigation. Inquiries concerning this study should be sent to P.G.G. at the University of Minnesota.
11
Paul G . Ga~sman,*~ Kenji Uneyama, Jerry L. Hahnfeld Department of Chemistry, University of Minnesota Minneapolis, Minnesota 55455 and Department of Chemistry, The Ohio State University Columbus, Ohio 43210 Receiued August 2. 1976
2
Photolysis of 1 in methanol with a 450-W Hanovia source gave as major products 37% of 2,33%of 11, and 10%of 4.7 The formation of 4 in this reaction indicated that some solvolysis was competing with the homolytic cleavage. The difference in the ratio of 2 to 1 1 may be attributed to the generation of a pair of amino radicals plus nitrogen in the irradiation of 2, vs. the formation of a chlorine-amino radical pair in the photolysis of 1. Since the precursors are different in the two experiments being compared, it is also conceivable that the generated amino radicals might not exist in identical solvent cages and, hence, may react with the solvent cage a t slightly different rates and in slightly different manners. From the photochemical decomposition of 8 and 1, it became obvious that 11 was a major product of the photochemically generated radical 7. However, it was not established whether the formation of 11 depended on 7 having its origin in a n excited state reaction. In order to answer this question, we carried out the methanolysis of 1 in the presence of 0.1 equiv of benzoyl peroxide. This reaction gave 10% of 2,5%of 3,26% of 4, and most significantly 21% of 11. Again, a combination of homolytic and heterolytic processes was involved. However, the formation of 11 in this reaction firmly established that 11 could arise from a nonphotochemically generated nitrogen radical. Journal of the American Chemical Society
Biosynthesis of the Isoquinuclidne Moiety of Dioscorine. Incorporation of [5,6-13C2]Nicotinic Acid Established by Means of I3C Nuclear Magnetic Resonance Sir: Dioscorine (2)' is an alkaloid found in the tropical yam, Dioscorea hispida, Dennst. and related species. W e have previously2 established that the administration of [ 1-I4C] acetate to this plant yielded radioactive dioscorine, which was labeled on alternate carbons (C-5, 10, and 12) of the unsaturated lactone ring. This result led us to suggest that dioscorine is formed by a condensation between AI-piperideine (1) (which is formed from lysine in higher plants3) with a branched 8carbon unit derived from four acetate units (route A, Scheme I). Spenser4 suggested a slight modification in which pelle-
/ 99:2 / January 19, 1977
